Compositions comprising fetal hemoglobin and bacterial endotoxin and optionally additional fetal liver components

Abstract

The present invention relates to a pharmaceutical composition representing a novel immunomodulating principle comprising bacterial endotoxin, fetal hemoglobin or more particularly a heme-free derivative or the γ-chain thereof, and optionally, components which are present in the fetal liver in addition to HbF. The composition is delivered to humans in a pharmaceutically acceptable carrier and/or diluent. In accordance with the present invention it was surprisingly found that endotoxin and fetal hemoglobin partial structures display a pronounced synergistic biomedical activity. The biomedical effect of fetal hemoglobin and its partial structures is surprisingly not based on a classical hemoglobin function as an oxygen transporter but related to a modulation of endotoxin-mediated bioactivity. This biomedical activity is surprisingly also observed after oral application of the composition. The composition of the invention finds a variety of applications which have in common the stimulation of the immune system and the reversion in polarization of cytokines and chemokines from a Th2-directed response to a Th1-type response. The proposed applications would therefore include the treatment of allergic conditions, malignancies, chronic infections, autoimmune phenomena and age-related imbalances.

1. A composition comprising:
 (a) endotoxin or an endotoxically active portion thereof, 
 (b) fetal hemoglobin, one or more single chains thereof, or one or more combinations of chains thereof, and 
 (c) a pharmaceutically acceptable carrier, diluent or excipient, 
 
       wherein the endotoxin or endotoxically active portion thereof; and the fetal hemoglobin, one or more single chains thereof, or one or more combinations of chains thereof; are present in amounts that synergistically enhance at least one endotoxin bioactivity, and wherein the composition is suitable for pharmaceutical administration. 
     
     
       2. The composition of  claim 1 , wherein said fetal hemoglobin, one or more single chains thereof or one or more combinations of chains thereof, is obtained from non-human fetal tissue. 
     
     
       3. The composition of  claim 2 , wherein said non-human fetal tissue is obtained from sheep, goat, horse or cow. 
     
     
       4. The composition of  claim 1 , further comprising a fetal liver peptide or glycopeptide. 
     
     
       5. The composition of  claim 4 , wherein said fetal liver peptide or glycopeptide is thioredoxin, ubiquitin, aldose 1-epimerase, alcohol dehydrogenase, prostaglandin-F synthase, prostaglandin-F synthase 2, regucalcin/senescence marker protein-30, thiosulfate sulfurtransferase, carbonyl reductase 1,3-hydroxyanthranilate 3,4-dioxygenase, guanidinoacetate-N-methyltransferase, carbonic anhydrase III, carbonic anhydrase II, catechol-O-methyltransferase (soluble isoform), phosphatidylethanolamine-binding protein, peptidyl-prolyl-cis-trans-isomerase A, cyclophilin A, superoxide dismutase, cellular retinol-binding protein I, glycine cleavage system H protein, putative 42-9-9 protein, hemoglobin gamma chain, hemoglobin alpha chain, fatty acid-binding protein (liver), macrophage migration inhibitory factor or acyl-CoA-binding protein. 
     
     
       6. The composition of  claim 1 , wherein said combination of chains is an α, γ-dimer of fetal hemoglobin. 
     
     
       7. The composition of  claim 1 , wherein said single chain is a γ-chain of fetal hemoglobin. 
     
     
       8. The composition of  claim 1 , wherein said one or more combinations of chains are free of heme. 
     
     
       9. The composition of  claim 1 , wherein said endotoxin is bacterial S- or R-form lipopolysaccharide (LPS). 
     
     
       10. The composition of  claim 1 , wherein said endotoxically active portion of endotoxin is the polysaccharide-free lipid A component obtained from LPS. 
     
     
       11. The composition of  claim 1 , wherein said endotoxin is natural or synthetic pentaacyl-lipid A, natural or synthetic hexaacyl-lipid A, or a combination thereof. 
     
     
       12. The composition of  claim 11 , wherein said natural or synthetic pentaacyl- or hexaacyl-lipid A is a monophosphate. 
     
     
       13. The composition of  claim 1 , wherein the ratio by weight of the fetal hemoglobin, single chains thereof or combinations of chains thereof component to the endotoxin or the endotoxically active portion thereof component ranges from 1:1 to 1000:1. 
     
     
       14. The composition of  claim 1  confectioned for oral administration. 
     
     
       15. A method for enhancing at least one endotoxin bioactivity in a subject, comprising the step of administering to the subject the composition of  claim 1 . 
     
     
       16. A composition comprising:
 (a) endotoxin or an endotoxically active portion thereof, 
 (b) fetal hemoglobin, one or more single chains thereof, or one or more combinations of chains thereof, and 
 (c) a pharmaceutically acceptable carrier, diluent or excipient, 
 
       wherein the ratio by weight of the fetal hemoglobin, single chains thereof or combinations of chains thereof component to the endotoxin or the endotoxically active portion thereof component ranges from 1:1 to 1000:1, and wherein the composition is suitable for pharmaceutical administration. 
     
     
       17. The composition of  claim 13  or  16  comprising between 0.001 and 10 mg of fetal hemoglobin, single chains thereof or combinations of chains thereof, and between 0.01 and 1000 μg of endotoxin or an endotoxically active portion thereof.